Certain 2,4 - diarylthiazole-5-alkanoic acids and derivatives thereof



United States Patent US. Cl. 260302 36 Claims ABSTRACT OF THE DISCLOSURE2,4-diarylthiazoles substituted at position by a polycarbon carboxylicacid group are useful as anti-inflammatory agents. The aryl groups maybe phenyl, tolyl, anisyl, halophenyl, naphthyl, thienyl or furyl, andthe acid group may be an acetic, propionic, or higher acid group Theproducts appear to be less ulcerogenic than anti-inflammatory agents nowin general use.

This invention relates to a novel group of thiazoles containing arylgroups in the 2- and 4-positions and an aliphatic acid group, or aderivative thereof, in the 5- position, to processes for the preparationthereof, to pharmaceutical compositions containing such thiazoles, andto the use of such compositions for the relief of inflammation.

The present invention provides 2,4-diarylthiazoles of the generalFormula I l T S N i and acid addition salts thereof, in which R and Rare the same or different and are substituted or unsubstituted arylgroups (which may be heteroaryl groups) and R is an aliphatic carboxylicacid radical containing at least two carbon atoms, or a derivativethereof. The radicals R and R may be monocyclic or bicyclic aromaticcarbocyclic radicals, (such as phenyl or naphthyl radicals) or may beheterocyclic aryl radicals (such as thienyl or furyl radicals) any ofwhich radicals may be substituted but for simplicity R and R arereferred to herein as aryl radicals. R may for example contain 2 to 6,prefearbly 2 to 4 carbon atoms, and can be a straight chain or branchedaliphatic acid radical, or a derivative thereof, e.g., an acetic,n-propionic, isopropionic, ni-butyric or isobutyric acid radical, or aderivative thereof, for example an ester or nitrile.

The compounds of the above general formula exhibit pharmacologicalactivity, for example anti-inflammatory activity as shown by test onlaboratory animals, and are intermediates in the preparation of othersubstituted thiazoles. Examples of tests which can indicate that acompound has anti-inflammatory activity are those described by Winter etal. in Proc. Soc. Exp. Biol. Med. III, 544 (1962); Buttle et al. inNature 179, 629 (1957); Konzett and Rossler in Arch. Path. Pharmac. 195,71 (1940) and Newbould in Brit. Journ. Pharm. Chemoth. 21, 127-137(1963).

The compounds of the above general formula may be prepared by suitablegeneral methods known for forming an appropriately substituted thiazolering, for example, by cyclising reactants appropriately substituted byradicals R R and R to form the said thiazole, if desired carrying outany after-reactions, and if desired forming an acid addition saltthereof.

Patented Nov. 4, 1969 Thus, an a-haloketone of the general Formula II(II) R O H-C-R I ll Hal 0 may be reacted with a thioamide of the generalFormula 111 II) E $11 IU-C-NH: or R C=NH in which R and R have themeanings defined above, Hal is a halogen atom, (for example chlorine orbromine) and R has the same meaning as R or is a radical convertiblethereto, (e.g., a carboxyl radical, a derivative thereof, or ahalomethyl radical) and if necessary the thiazole obtained is convertedto a desired thiazole of general Formula I.

The a-haloketones of general Formula II can be prepared in known manner,for example by halogenating (e.g., brominating) the products ofFriedel-Crafts reactions between optionally substituted aromatic (orheteroaromatic) hydrocarbons and appropriate anhydrides, e.g., succinic,glutaric or methyl succinic anhydride. Ether has been preferred assolvent for the halogenation. The thioamides of general Formula IIIgenerally may be prepared by the method of Fairfull et al. (Journal ofthe Chemical Society 1952, 742) from the corresponding nitriles.

We have found it particularly convenient to react an acid of generalFormula II, (i.e., R contains 9. --COOH group and preferably is anacetic or propionic acid group), in which Hal is a bromine atom with theappropriate thioamide. The reaction is preferably carried out in asolvent at room temperatures or above, e.g., up to the boiling point ofthe solvent. When the reaction is carried out in the absence of a baseand in the present of an alcohol, for example ethanol, the productobtained generally is the ester which can be hydrolysed to the acid ifdesired. On the other hand if another solvent is used, or if an alcohol(preferably isopropanol) is used as solvent in the presence of a base(e.g., analkali metal carbonate) the acid group R generally is obtaineddirectly, thus avoiding the necessity of having to effect a hydrolysisif the acid is desired. It is preferable to add the base (for exampleanhydrous sodium carbonate) to the reaction mixture at the start of thereaction as this generally improves the yield and/or assists inseparating the desired product.

Alternatively, phosphorus pentasulphide may be used to cyclise ana-acylamino carbonyl compound of the general formula:

(IV) R4CCHR9 in which R and R and R have the meanings defined above and,if necessary to radical R can then be converted to a radical R Thecyclisation reaction generally may be carried out at room temperaturesor above, e.g., temperatures of from 15 C. to the boiling point of thesolvent used.

The compounds of general Formula IV may be prepared by reacting acompound of the formula:

(which may be made by reacting an aryl actic ester with an alkali aceticester and halogenating the product) with a salt of an amide of thegeneral formula:

R C NHz R R Hal and R having the meanings defined above.

When R is a -COOH radical or a derivative thereof, or a halomethylradical in either of the above processes, the product initially obtainedis a thiazole of general Formula I but in which R is replaced by theradical R In such cases the radical R then has to be converted to aradical R to give a compound of general Formula I, by means of ahomologation reaction. For example, if R is a carboxyl radical,homologation may be effected by an Arndt-Eistert reaction by forming thecorresponding acid halide, reacting this with diazomethane, and treatingthe diazoketone formed with water and a catalyst (e.g., colloidalsilver). Similarly, when R is a halomethyl radical, reaction with acyanide (e.g., potassium cyanide) yields the nitrile which can behydroysed.

After preparing a thiazole of general Formula I, the radical R mayoptionally be converted to another radical R in known manner. Forexample, if R is an aliphatic acid nitrile or amide radical, the acidcan be obtained therefrom, if desired, by hydrolysis. The ester can beobtained from the acid by reaction with an alcohol, and the hydroxamicacid derivative can be obtained from an ester by reaction withhydroxylamine. An acyloxymethyl ester can be obtained by reacting theacid or a salt thereof (e.g., an alkali metal or amine salt) with anacyloxymethyl halide such as an acetoxymethyl halide. The amide can beobtained from the nitrile by hydrolysis, from the acid or a functionalderivative thereof by reaction with ammonia or from the ammonium salt byheating.

It is apparent that if substituents are present in the aryl rings of thestarting materials, they should be inert to the reactions carried out.If necessary, a reactive substituent (e.g. an amino radical) can beblocked by standard methods while the reaction is being carried out andthe blocking agent removed at the end of the reaction.

Examples of aryl radicals R and R are phenyl, naphthyl, thienyl andfuryl radicals, such as unsubstituted phenyl or phenyl substituted byhalogen (e.g., fluorine, chlorine, or bromine), lower alkyl radicalscontaining up to 6 and preferably up to four carbon atoms (e.g., methyl,ethyl, propyl, isopropyl, n-isobutyl), lower alkoxy radicals containingup to 6 and preferably up to 4 carbon atoms (e.g. methoxy, ethoxy andpropoxy), amino substuted amino (e.g. dimethylamino), nitro or bytrihalomethyl (e.g., trifiuoromethyl) radicals, or substituted orunsubstituted naphthyl, thienyl or fulyl radicals (e.g., 1- orZ-naphthyl, 2- or 3-thienyl or 2 or 3-furyl). When substituents arepresent in the phenyl rings, they can occupy positions numbered from 2to 6 around the phenyl rings. Preferably, R is acetic or a propionicacid, or a derivative for example a salt, ester, amide or hydroxamicacid derivative thereof.

The 2,4-diaryl thiazoles provided by the invention contain a basic ringnitrogen atom capable of forming acid addition salts withpharmaceutically acceptable acids and the invention also provides suchsalts.

The invention further provides a pharmaceutical composition whichcomprises a pharmaceutically active form of a compound provided by theinvention and a non-toxic carrier. The pharmaceutically active formgenerally is when R contains a carboxyl group, which may be in amide orsalt form. An suitable carrier known in the art can be used.

In such a composition the pharmaceutically acceptable carrier can be asolid or a sterile liquid. Solid form compositions include powders,tablets and capsules. A solid carrier can be one or more substanceswhich may also act as flavouring agents, lubricants, solubilizers,suspending agents, binders, or tablet-disintegrating agents; it can alsobe an encapsulating material. In powders the carrier is a finely dividedsolid which is in admixture with the finely divided active ingredient.In tablets the active ingredient is mixed with a carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 to 99, preferably 10-80% of the active ingredient. Suitable solidcarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. Theterm composition is intended to include the formulation of an activeingredient with encapuslating material as carrier to give a capsule inwhich the active ingredient (with or without other carriers) issurrounded by carrier, which is thus in association with it. Similarlycachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredients can be dissolvedor suspended in a pharmaceutically acceptable sterile liquid carrier,such as sterile water, sterile organic solvent or a mixture of both.Perferably a liquid carrier is one suitable for parenteral injection.Where the active ingredient is sufi'iciently soluble it can be dissolvedin normal saline as a carrier: if it is too insoluble for this it canoften be dissolved in a suitable organic solvent, for instance aqueouspropylene g ycol or polyethylene glycol solutions. Aqueous propyleneglycol containing from 10 to 75% of the glycol by weight is generallysuitable. In other instances compositions can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxymethyl cellulose solution, or in a suitable oil, for instancearachis oil. Liquid pharmaceutical compositions which are sterilesolutions or suspensions can be utilized by intramuscular,intraperitoneal or subcutaneous injection. In many instances a compoundis orally active and can be administered orally either in liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form. Insuch form, the composition is sub-divided in unit doses containingappropriate quanities of the active ingredient; the unit dosage form canbe a packaged composition, the package containing specific quantities ofcompositions, for example packeted powders or vials or ampoules. Theunit dosage form can be a capsule cachet or tablet itself, or it can bethe appropriate number of any these in packaged form. The quantity ofactive ingredient in a unit dose of composition may be varied oradjusted according to the particular need and the activity of the activeingredient.

The following non-limiting examples illustrate the invention.

EXAMPLE 1 4-( 2'-thienyl -2- 2'-methyphenyl -thiazol-5-ylacetic acidZ-methyltiobenzamide (5.7 g.), 3-bromo-3-(2'-thenoyl) propionic acid (10g.) and anhydrous sodium carbonate (1.8 g.) were heated together inisopropanol (55 ml.) with stirring at 60 C. for 30 minutes. The mixturewas then cooled to 40 C. and stirred for a further 60 minutes. Aftercooling to room temperature, the mixture was allowed to stand overnightand poured slowly into cold water (1 litre). A few drops of cone.hydrochloric acid Were added to make the mixture acid and, afterstanding for a further 30 minutes, the resulting solid was filtered off.The aqueous phase was extracted with ether and the extracts combinedwith the solid. The ethereal solution was extracted thoroughly withsaturated aqueous sodium bicarbonate solution and the aqueous extractsacidified with cone. hydrochloric acid. The oily precipitate from theaqueous phase quickly solidified and, after drying, was recrystallizedfrom benzene. Yield: 6.7 g. (46.2% MJP. 136-8 C.

Analysis.--Found: C, 61.0; H, 4.2; N, 4.3; S, 20.3, C H NO S requires C,60.9; H, 4.2; N, 4.4; S, 20.3%

EXAMPLE 2 2-(4'-chlorophenyl) -4- (4'-rnethoxyphenyl thiazol-S- ylaceticacid 2-(4'-chlorophenyl)-4-phenylt.hiazol-5-ylacetic acid Following theprocedure of Example 1, 4-ch1orothiobenzamide (14.6 g.) and3-benzoyl-3-bromopropionic acid (21.8 g.) were reacted together inisopropanol (127 ml.) in the presence of soid-um carbonate (4.3 g.).After working up in the manner described in that example andrecrystallizing from benzene, the title compound (12.4 g., 44.2) of M.P.153-5 C. was obtained.

Analysis.Found: C, 62.1; H, 3.8; N, 4.1; S, 9.8; Cl, 10.8. C H 'ClNO- srequires C, 61.9; H, 3.7; N, 4.3; S, 9.7; Cl, 10.8%.

EXAMPLE 4 2- (4'-chlorophenyl) -4- 2' -thienyl) thiazol-S -yl aceticacid Following the procedure of Example 1, 4-chlorothiobenzamide (6.3g.) and 3-bromo-3-(2'-thenoyl)-propionic acid (10 g.) were reactedtogether in isopropanol (55 ml.) in the presence of sodium carbonate(1.8 g.). After working up in the manner described in that example andrecrystallizing from benzene, the title compound (4.8 g., 31.2%) of M.P.1379 C. was obtained.

Analysis.Found: C, 53.6; H, 3.2; N, 4.0; S, 19.0; CI, 10.5. C H ClNO Srequires C, 53.6; H, 3.0; N, 4.2; S, 19.1; C1, 10.6%.

EXAMPLE 5 2,4-di-(4-methoxyphenyl)thiazol-S-ylacetic acid Following theprocedure of Example 1, 4-me-thoxythiobenzamide (6.0 g.) and3-bromo-3-(4-methoxybenzoyl)- propionic acid (10.3 g.) were reactedtogether in isopropanol (50 ml.) in the presence of sodium carbonate(1.8 g.). After working up as described in that example andrecrystallizing from glacial acetic acid/water, the title compound (8.0g., 56.3%) of M.P. 176-8 C. Was obtained.

Analysis.Found: C, 64.3; H, 5.0; N, 3.9; S, 9.1. C H NSQ, requires C,64.2; H, 4.8; N, 3.9; S, 9.0%.

EXAMPLE 6 4 (4-methoxyphenyl) -2- 2'-met.hylphenyl) thiazol-S ylaceticacid Following the procedure of Example 1, 2-methylthiobenzamide (5.4g.) and 3-bromo-3-(4'-methoxybenzoyl)- propionic acid (10.3 g.) werereacted together in isopro panaol (50 ml.) in the presence of sodiumcarbonate (1.8 g.). After working up as described in that example, thetitle compound (5.4 g., 44.6%) of M.P. 140-1" C. was obtained.

Analysis.-Found: C, 67.2; H, 5.1; N, 4.3; S, 9.4. C H NSO requires C,67.2; H, 5.1; N, 4.1; S, 9.5%.

EXAMPLE 7 2-(2-methylphenyl)-4-phenylthiazol-5-ylacetic acid2-methylthiobenzamide (7.5 g.), 3-benZoyl-3-bromopropionic acid (12.85g.) and isopropanol (75 ml.) were heated together with stirring for 30minutes at 60 C. After cooling to 40 C., anhydrous sodium carbonate (2.5g.) was added to the orange-colored solution and the mixture held at 40C. for a further 60 minutes. After standing overnight the reactionmixture was poured slowly with stirring into cold water (1 litre) and afew drops of cone. hydrochloric acid added to make the mixture acidic.After standing for 30 minutes, the oily semi-solid layer was separatedand retained. The aqueous phase was extracted with ether and theextracts combined with the oily layer. The resulting ether solution wasextracted thoroughly with saturated aqueous sodium bicarbonate solutionand the aqueous extracts acidified with cone. hydrochloric acid. Theresulting oily precipitate quickly solidified and after drying wasrecrystallized from benzene petroleum ether (60-80 C.) to give the titlecompound (3.0 g., 19.4%), M.P. 165-7 C.

Analysis.-Found: C, 69.7; H, 5.0; N, 4.4; S, 10.5. C H NO S requires C,69.9; H, 4.9; N, 4.5; S, 10.4%.

EXAMPLE 8 2-(3'-methy1phenyl) -4-phenylthiazol-5-ylacetic acid Followingthe procedure of Example 7, 3-methylthiobenzamide (7.5 g.),3-benzoyl-3-bromopropionic acid (12.85 g.), isopropanol (75 ml.) andsodium carbonate (2.5 g.) were used to obtain the title compound whichwas recrystallizedfrom benzene/petroleum ether. Yield. 2.3 g. (15%) M.P.123-5 C.

Analysis.-Found: C, 69.7; H, 4.9; N, 4.5; S, 10.3. C H NO S requires C,69.9; H, 4.9; N, 4.5; S, 10.3%.

EXAMPLE 9 2-(4'-methoxyphenyl)-4-phenylthiazol-5-ylacetic acid Followingthe procedure of Example 7, 4-methoxythiobenzamide (8.35 g.),3-benzoyl-3-bromopropionic acid (12.85 g.), isopropanol (75 ml.) andsodium carbonate (2.5 g.) were used to obtain the title compound, whichwas recrystallized from benzene. Yield: 6.6 g. (40.6%) M.P. 149.5-152 C.

Analysis.-Found: C, 66.4; H, 4.6; N, 4.2; S, 9. C H NO S requires C,66.4; H, 4.7; N, 4.3; S, 9.9%.

EXAMPLE 10 2-(2'-chlorophenyl) -4-phenylthiazol-5-ylacetic acidFollowing the procedure of Example 7, 2-chlorothiobenzamide (8.60 g.),3-benzoyl-3-bromopropionic acid (12.85 g.), isopropanol (75 ml.) andsodium carbonate (2.5 g.) were used to obtain the title compound, whichwas recrystallized from benzene. Yield: 4.6 g. (27.6%), M.P. 16871 C.

Analysis.-Found: C, 62.0; H, 3.7; N, 4.2; S, 9.9; Cl, 10.8. C H CINO Srequires C, 61.9; H, 3.7; N, 4.3; S, 9.7;C1, 10.8%.

EXAMPLE 11 2-(4-methylphenyl) -4-phenylthiaz0l-5-ylacetic acid Followingthe procedure of Example 7, 4-methylthiobenzamide (7.5 g.)3-benzoyl-3-bromopropionic acid (12.85 g.), isopropanol (75 ml.) andsodium carbonate (2.5 g.) were used to obtain the title compound, whichwas recrystallized from benzene. Yield: 7.9 g. (51.2%), M.P. 1701 C.

Analysis.Found: C, 70.1; H, 5.0; N, 4.3; S, 10.5. C H NO S requires C,69.9; H, 4.9; N, 4.5; S, 10.4%.

EXAMPLE 12 2-( 1'-naphthyl) -4-phenylthiazol-5 -ylacetic acid Followingthe procedure of Example 7, l-thionaphthamide (14.1 g.),3-benzoyl-3-bromopropionic acid (19.3 g.), isopropanol ml.) and sodiumcarbonate (3.75 g.) were used to obtain the title compound, which wasrecrystallized from benzene/ petroleum ether. Yield: 8.6 g. (29.7% M.P.-8 C.

7 Analysis.Found: C, 73.1; H, 4.4; N, 4.1; S, 9.3. C21H13NO2S requiresC, H, N, S, 9.3%.

EXAMPLE 13 2- 3'-trifiuoromethylphenyl -4-phenylthiazol-5- ylacetic acidFollowing the procedure of Example 7, 3-trifluor0methylthiobenzamide(15.3 g.), 3-benzoyl-3-bromopropionic acid (19.3 g.) isopropanol (115ml.) and sodium carbonate (3.75 g.) were used to obtain the titlecompound, which was recrystallized from benzene/petroleum ether. Yield:6.4 g. (23.4%), M.P. 143-5 C.

Analysis-Found: C, 59.6; H, 3.7; N, 3.8; F, 15.6; S, 8.6. C H F NO Srequires C, 59.6; H, 3.3; N, 3.9; F, 15.7; S, 8.8%.

EXAMPLE 14 4- (2'-thienyl) -2- 4'-methoxyphenyl thiazol-S- ylacetic acidFollowing the procedure of Example 7, 4-methoxythiobenzamide (6.3 g.),3-bromo-3-(2-thenoyl)-propionic acid (10.0 g.), isopropanol (55 m1.) andsodium carbonate (1.8 g.) were used to obtain the title compound, whichwas recrystallized from benzene. Yield 1.9 g. (13.3%), M.P. 149-151 C.

Analysis.FOund: C, 58.0; H, 3.9; N, 4.3; S, 19.5. C H NO S requires C,58.0; H, 4.0; N, 4.2; S, 19.4%.

EXAMPLE 15 2-(2-naphthyl)-4-phenylthiazol-5-ylacetic acid Following theprocedure of Example 7, 2-thionaphthamide (14.1 g.),3-benzoyl-3-bromopropi0nic acid (19.3 g.), isopropanol (115 ml.) andsodium carbonate (3.75 g.), were used to obtain the title compound,which was recrystallized from benzene. Yield: 14.0 g. (50.6% M.P. 171-2C.

Analysis.Found: C, 72.9; H, 4.6; N, 3.9; S, 9.2; C H NO S requires C,83.2; H, 4.4; N, 4.0; S, 9.3%.

EXAMPLE 16 2-(4-methoxyphenyl) -4-(2'-naphthyl) thiazol-S-ylacetic acidFollowing the procedure of Example 7, 4-methoxythiobenzamide (22.5 g.),3-brom0-3-(2'-naphthoyl)propionic acid (40.5 g.), isopropanol (200 ml.)and sodium carbonate (6.6 g.) were used to obtain the title compound,which was recrystallized from glacial acetic acid/water. Yield: 22.4 g.(44.4%), M.P. 160-162 C.

Analysis.Found: C, 70.3; H, 4.5; N, 3.7; S, 8.4. C H NSO requires C,70.4; H, 4.6; N, 3.7; S, 8.5%.

EXAMPLE 17 B- 2- 4'-chlorophenyl -4-phenylthiazol-5-yl] propionic acid4-benzoyl-4-br0mobutyric acid (26.5 g.) and 4-chlorothiobenzamide (16.7g.) were heated together in refluxing ethanol (80 ml.) for 3 /2 hours.After cooling, the solvent was evaporated, and the residue was extractedinto benzene. The" benzene solution was washed with 2 N sodium carbonatesolution, water, and then dried (MgSO and evaporated to give the ethylester of fi-[2-(4'-chlor0phenyl) 4 phenylthiazol-S-yl]propionic acid asa yellow oil (39.0 g.).

The ester was dissolved in warm ethanol (50 ml.) and treated with asolution of potassium hydroxide (5.7 g.) in ethanol (50 ml.). After 1hour, most of the solvent was evaporated and water was added, followedby 2 N hydrochloric acid to adjust pH to 4. The mixture was extractedwith ether, and the combined extracts were washed with 2 N sodiumcarbonate solution. The alkaline solution was then acidified andextracted with ether. The ether solution was washed with water, dried(MgSO and evaporated to give {3-[2-(4'-chlorophenyl)-4-phenylthia- 8zol-5-yl]propionic acid as a solid (12.6 g., 37%). Recrystallizationfrom benzene gave needle crystals, M.P. 177-178 C.

Analysis.-Found: C, 63.0; H, 4.2; N, 4.0; S, 9.4; Cl, 10.1. C H CINO Srequires C, 62.9; H, 4.1; N, 4.1; S, 9.3; Cl, 10.3%.

EXAMPLE 18 4-(1-naphthyl)-2-phenylthiazol-S-ylaeetic acid Following theprocedure of Example 17, 3-bromo-3- (1'-naphthyl) propionic acid (30.7g.) and thiobenzamide (13.7 g.) were reacted together in ethanol to give34.2 g. of the crude ethyl ester, which was hydrolysed to the acid. Thiswas then recrystallized from benzene to yield 4.2 g. (12%) of the titlecompound, M.P. 166-167 C.

Analysis.Found: C, 73.0; H, 4.6; N, 4.0; S, 9.4. C H NSO requires C,73.1; H, 4.4; N, 4.1; S, 9.3%.

EXAMPLE 19 4-(2-naphthyl)-2-phenylthiazol-5-ylacetic acid Following theprocedure of Example 17, methyl 3- bromo-3-(2-naphthyl)propionate (29.6g.) and thiobenzamide (12.6 g.) were reacted together in ethanol to givethe crude methyl ester (31.8 g.), which was then hydrolysed to the acid.Recrystallization from benzene yielded 9.9 g. (31%), M.P. 168-169 C.

Analysis.-Found: C, 73.0; H, 4.4; N, 4.0; S, 9.4. C H NSO requires C,73.1; H, 4.4; N, 4.1; S, 9.3%.

EXAMPLE 20 2,4-diphenylthiazol-5-ylacetic acid ethyl ester3-bromo-3-benzoylpropionic acid (40 g.) and thiobenzamide (21.3 g.) wereheated together in refluxing ethanol (500 ml.) for 8 hours. Most of theethanol was then evaporated, and a solution of sodium carbonate (10 g.)in water (300 ml.) was added. The mixture was extracted with ether, theether extracts were combined, washed with water, dried over Na SO andevaporated to give pale yellow needle crystals (46.1 g.), M.P. -91 C.Recrystallization from ethanol gave the pure ester (35.2 g., 70%), M.P.-96 C. as colorless needles.

Analysir.Found: C, 70.6; H, 5.2; N, 4.3; S, 10.1. C H NO S requires C,70.6; H, 5.3; N, 4.3; S, 9.9%.

EXAMPLE 21 2-phenyl-4-(4'-methoxyphenyl)thiazol-S- ylacetic acid ethylester Using the procedure shown in Example 20, 3-bromo-3-(4'-methoxybenzoyl)-propionic acid (11 g.) and thiobenzamide (5.25 g.)were reacted to give 2-phenyl-4-(4'- methoxyphenyl)-thiazol-5-ylaceticacid ethyl ester which recrystallized from ethanol as colorless needles(8.3 g., 62%) M.P. 67.5-68.5 C.

Analysis.-Found: C, 68.0; H, 5.4; N, 3.9; S, 9.2. C H NO S requires C,68.0; H, 5.4; N, 4.0; S, 9.1%.

EXAMPLE 22 2-phenyl-4- 4-chlorophenyl thiozol-5- ylacetic acid ethylester Using 'the procedure shown in Example 20, 3-bromo-3-(4'-chlorobenzoyl)-propionic acid (29.2 g.) and thiobenzamide (13.7 g.)were reacted to give 2-phenyl-4-(4'- chlorophenyl)thiazol-S-ylaceticacid ethyl ester which recrystallized from ethanol as colorless needles(19.9 g., 56%), M.P. 69-70 C.

Analysis.--Found: C, 63.8; H, 4.7; N, 3.8; S, 9.1. C H ClNO S requiresC, 63.7; H, 4.5; N, 3.9; S, 9.0%.

EXAMPLE 23 2,4-diphenylthiazol-5-ylacetic acid2,4-diphenylthiazol-S-ylacetic acid ethyl ester (15 g.) was dissolved inwarm ethanol ml.) and potassium hydroxide (10 g.) in water (20 ml.) wasadded. After 1 hour most of the ethanol was evaporated, and the solutionwas diluted with water. Concentrated hydrochloric acid was then addeduntil the mixture was just acid, and the oily solid was extracted inether. The ether extracts were combined, washed with water, dried overNa SO and evaporated to give a viscous oil (13.5 g.) which slowlycrystallized. Recrystallization from benzene gave colorless needlecrystals of the acid (12.2 g., 89%) M.P. 152-153" C.

Analysis.Found: C, 69.4; H, 4.2; N, 4.7; S, 10.8. C H NO S requires C,69.2; H, 4.4; N, 4.7; S, 10.9%.

EXAMPLE 24 2-phenyl-4-(4'-methoxyphenyl)thiazol-S-ylacetic acid Usingthe procedure shown in Example 23, the ethyl ester g.) was hydrolysed to2-phenyl-4-(4'-meth0xyphenyl)-thiazol-5-ylacetic acid whichrecrystallised from benzene as colorless needles (3.9 g., 85%) M.P.178.5- 179.5 C.

Analysis.Found: C, 66.5; H, 4.5; N, 4.3; S, 10.0. C H NO S requires C,66.5; H, 4.6; N, 4.3; S, 9.9%.

EXAMPLE 25 2-pheny1-.4-(4'-chlorophenyl)thiazol-S-ylacetic acid Usingthe procedure shown in Example 23, the ethyl ester g.) was hydrolysed to2-phenyl-4-(4'-chlorophenyl)-thiazol-5-ylacetic acid whichrecrystallized from benzene as colorless needles (4.9 g., 63%) M.P. 161-162 C.

Analysis.-Found: C, 62.0; H, 3.7; N, 4.2; S, 9.8; Cl, 10.7. C H ClNO Srequires C, 62.0; H, 3.7; N, 4.2; S, 9.7; Cl, 10.7%.

EXAMPLE 26 a-(2,4-diphenylthiazol-5-yl) propionic acid3-bromo-3-benzoy1isobutyric acid (13.6 g.) and thiobenzamide (6.9 g.)were heated in isopropanol (75 ml.) at 60 C. for 30 minutes. Sodiumcarbonate (2.5 g.) was then added, and heating was continued for afurther 10 minutes. After standing overnight the mixture was dilutedwith water, and then the aqueous solution was decanted from theresulting oil. The oil was taken up in ether and extracted with diluteaqueous sodium carbonate solution. The basic extract was washed withether, acidified with hydrochloric acid to pH 4 and then the resultingoil was extracted with ether. The ether extract was Washed with water,dried over Na SO and evaporated to give a pale yellow viscous oil whichslowly crystallized. Recrystallization from glacial acetic acid-watergave a-(2,4-diphenylthiazol-5-yl)-propionic acid as prismatic crystals(8.6 g., 55%) M.P. 142-144 C.

Analysis.Found: C, 69.9; H, 4.9; N, 4.7; S, 10.3. C H NO S requires C,69.9; H, 4.9; N, 4.9; S, 10.3%.

EXAMPLE 27 2-phenyl-4- (2'-thienyl thiazol-S-ylacetic acid Using theprocedure described in Example 26, 3-=bromo- 3-(2-thenoyl)propionic acid(13.2 g.) and thiobenzamide (6.9 g.) were reacted to give2-phenyl-4-(2'-thienyl) thiazol-S-ylacetic acid (7.2 g., 48%) as needlecrystals M.P. 1345-1350 C.

Analysis.-Found: C, 59.9; H, 3.7; N, 4.5; S, 21.0. C15H11NO2S2 requiresC, H, N, S, 21.3%-

EXAMPLE 28 2-phenyl-4-(4'-methylphenyl)thiazol-S-ylacetic acid Using theprocedure described in Example 26, 3-bromo-3-(4'-methylbenzoyl)propionic acid (27.1 g.) and thiobenzamide (13.7 g.)were reacted to give 2-phenyl-4-(4- methyl henyl)thiazol-S-ylacetic acid(9.6 g., 31%) M.P. 168-169 C. from benzene.

Analysis.Found: C, 70.0; H, 5.1; N, 4.6; S, 10.6. C H NO S requires C,69.9; H, 4.9; N, 4.5; S, 10.3%.

EXAMPLE 29 2- (4 -me thoxy phenyl -4-phenylthiazol5 -ylace tic acidethyl ester 4-methoxythiobenzamide (4.2 g.) and 3-benzoyl-3bromopropionic acid (6.4 g.) were refluxed in ethanol (50 ml.) for 1 /2hours. After standing overnight at room temperature a crystalline solidseparated. The Whole of the reaction mixture was poured into water withstirring and the oily layer separated. The aqueous layer was washed withether (3x200 ml.) and the extracts combined with the oil. The ethersolution was washed with sodium bicarbonate solution dried overanhydrous sodium sulphate and evaporated to dryness. The resultingyellow oil quickly crystallized to a pale yellow crystalline solid.Recrystallization from industrial methylated spirits gave a pale yellowywhite solid (3.8 g., 43%) M.P. 60.562 C.

EXAMPLE 30 3- [2- (4'-methoxyphenyl -4-phenylthiazol-5-yl] propionicacid Following the procedure of Example 17, 4-benzoyl-4- brornobutyricacid (27.1 g.) and 4-methoxythiobenzamide (16.7 g.) were reactedtogether in ethanol to give the crude ethyl ester (39.5 g.) which wasthen hydrolysed to the acid. Recrystallization from benzene yielded 6.9g. (21%), M.P. 174 C.

Analysis-Found: C, 67.1; H, 5.0; N, 4.0; S, 9.6. C H NO S requires C,67.2; H, 5.1; N, 4.1; S, 9.4%.

EXAMPLE 3 1 Following the procedure of Example 17, 4-benzoyl-4-bromobutyric acid (27.1 g.) and Z-methylthiobenzamide (15.1 g.) werereacted together in ethanol to give the crude ethyl ester (37.5 g.),which was then hydrolysed to the acid. Recrystallization from benzeneyielded 5.7 g. (18%), M.P. 107l09 C.

Analysis.Found: C, 70.6; H, 5.4; N, 4.2; S, 9.8. C H NO S requires C,70.6; H, 5.3; N, 4.3; S, 9.9%.

EXAMPLE 32 2,4-diphenylthiazol-5-ylacetic acid methyl ester3-benzoyl-3-bromopropionic acid (29.5 g.) and thiobenzamide (15.7 g.)were heated together for 5 hours in refluxing methanol (300 ml.). Oncooling, needle crystals gg g 70%) of the methyl ester separated, M.P.122

Analysis.Found: N, 4.5; S, 10.6. O l-1 N0 5 requires N, 4.5; S, 10.3%.

EXAMPLE 33 8-(2,4-diphenylthiazol-5-yl)propionic acid4-benzoyl-4-bromobutyric acid (27.1 g.) and thiobenzamide were heated inrefluxing methanol (300 ml.) for 6 hours. Most of the methanol was thenevaporated and water was added. The resulting mixture was extracted withether, and the combined extracts were washed with sodium carbonatesolution, water and then dried Evaporation of the solvent gave themethyl ester of [ti-(2,4- diphenylthiazol-S-yl)propionic acid (23.3 g.)as a yellow oil.

The ester was dissolved in warm ethanol (200 ml.) and treated with asolution of potassium hydroxide (10 g.) in water (20 ml.). After 1 /2hours, the solution was partially evaporated and then poured into water.Acidification with cone. hydrochloric acid yielded an oil which wasextracted with ether. The combined extracts were washed with water,dried (Na SO and evaporated to give an oil which slowly solidified (15.6g., 50%). Re-

1 1 crystallization from ethanol gave the acid as long colorlessneedles, M.P. 150 C.

Analysis.-Found: C, 69.6; H, 5.0; N, 4.4; S, 10.2. C H NO S requires C,69.9; H, 4.9; N, 4.5; S, 10.3%.

EXAMPLE 34 2,4-diphenylthiazol-5-ylacetamide Methyl2,4-diphenylthiazol-5-ylacetate (1.9 g.) in methanol (25 ml.) and 0.88ammonium hydroxide solution (25 ml.) was heated in a sealed tube at 90C. for 5 hours. On cooling, needle crystals of the amide (0.6 g., 33%)were filtered oflF. Recrystallization from benzene gave long needles,M.P. 209-210 C.

Analysis.Found: C, 69.1; H, 4.9; N, 9.7; S, 11.0. C H N OS requires C,69.5; H, 4.8; N, 9.5; S, 10.9%.

EXAMPLE 35 4- (4'-chlorophenyl -2-phenylthiazol-5-ylacetamide4-(-4'-chlorophenyl) 2 phenylthiazol-S-ylacetic acid (2.0 g.) in drytetrahydrofuran (50 ml.) was cooled at C. and then dry triethylamine(0.68 g.) followed by ethylchloroformate (0.73 g.) were added dropwise;the temperature of the reaction was maintained between 05 C. to give themixed anhydride. After 0.5 hours, aqueous ammonia (0.35 g., 5.6. 0.88)was added dropwise. The mixture was stirred at room temperatureovernight (14 hours) and then evaporated to dryness. Water and ethylacetate were added to the solid, and the ethyl acetate layer wasseparated, dried (MgSO and evaporated to give a solid. The solid waswashed well with benzene to leave needle crystals of the amide (0.32 g.,15%), M.P. 223-4 C.

Following the procedure of Example 34 or 35, other amides according tothe invention can be made, including 2phenyl-4-(2-thienyl)thiazol-S-ylacetamide, B-[2-(4- chlorophenyl) 4phenylthiazol-S-yl]propionamide, 4- (2-thienyl) 2(2-methylphenyl)-thiazol-5-ylacetamide anda-(2,4-diphenylthiazol--yl)propionamide.

EXAMPLE 36 2-(2'-methoxyphenyl)-4-phenylthiazol-5-ylacetic acid 2methoxythiobenzamide (4.20 g.), 3 benzoyl-3- bromopropionic acid (6.40g.) and anhydrous sodium carbonate (1.25 g.) were added to isopropanol(40 ml.) and the mixture heated with stirring at 60 C. for 30 mins.After a further 1 hour at 40 C. the mixture was cooled to roomtemperature and poured into water (500 ml.). The mixture was acidifiedby the addition of a few drops of concentrated hydrochloric acid and athick oil separated. The aqueous phase was extracted with ether (2x100ml.) and the axtracts combined with the oil. The resulting solution wasextracted with saturated sodium bicarbonate solution (3x100 ml.) and theextracts acidified with concentrated hydrochloric acid. The resultingpale yellow solid was filtered off, dried, and recrystallized fromglacial acetic acid/water. Yield 6.4 g. (78.3%); M.P. 179l80.5 C.

Analysis.Found: C, 66.4; H, 4.6; N, 4.5; S, 9.8. C H NO S requires C,66.45; H, 4.65; N, 4.3; S, 9.8%.

EXAMPLE 37 2- (4-chl0ro-2-methoxyphenyl) -4-phenylthiazol-5- ylaceticacid (a) The procedure of Example 36 was followed, but using 4-chloro 2methoxythiobenzamide (50 g.), 3- benzoyl 3 bromopropionic acid (6.4 g.),anhydrous sodium carbonate (1.25 g.) and isopropanol (40 ml.) to givethe title compound. Yield 4.5 g. (64.6%) M.P. 204-5 C.

Analysis.Found: C, 58.9; H, 3.9; N, 3.8; Cl, 10.1; S, 9.2- C13H14CINO3Srequires C, H, 3.9; N, 3.9; Cl, 9.85; S, 8.9%.

(b) The 4 chloro 2 methoxythiobenzamide used as starting material wasprepared as follows. (This method is generally applicable to thepreparation of the thioamides.)

4-chloro-2-methoxybenzonitrile (26.5 g.) was dissolved in a mixture ofdry pyridine (22 ml.) and triethylamine (21 ml.) and hydrogen sulphidepassed through the mixture until the nitrile had been completelyconverted to the thioamide (about 15 hours). The reaction mixture waspoured into water (500 ml.) and the resulting precipitate filtered 01f.After air drying, the product was recrystallized from benzene. Yield24.1 g. (75.7%) M.P. 149-150 C.

Following the synthetic methods above examplified, 2 (2 chloro 6'methylphenyl)-4 phenylthiazol-5- ylacetic acid (M.P. 217-9 C.), 2 (4'methoxy-2'- methylphenyl 4 phenylthiazol 5 ylacetic acid (M.P. 136-8C.), 2 (2,6' dichlorophenyl) 4 phenylthiazol-S-ylacetic acid (M.P. 147-9C.), 4 phenyl 2- (2,6'-dimethylphenyl)thiazol 5 ylacetic acid (M.P.203-5 C.), 2-4-chloro-2'-methylphenyl 4 phenylthiazol 5 ylacetic acid(M.P. -7 C.), 4-(2- napthyl) 2 (2-rnethylphenyl)thiazol-S-ylacetic acid(M.P. l712 C.), 2-(2',4'-dimethoxyphenyl)-4-phenylthiazol 5 ylaceticacid (M.P. l579 C.), 2-(4-N,N- dimethylaminophenyl) 4 phenylthiazol 5ylacetic acid (M.P. 144-6 C.), 2 (2,3-dimethylphenyl)-4- phenylthiazol 5-'ylacetic acid (M.P. 143-5 C.), 2- (2-4 dichlorophenyl) 4 phenylthiazolS ylacetic acid (M.P. 158-160 C.), 2,4 di-(4 chlorophenyl) thiazol 5ylacetic 'acid methyl ester and 2,4-di-(4'- chlorophenyl)thiazol 5ylacetic acid (M.P. 175-7" C.), were also prepared.

Other compounds of general Formula I which can be prepared following thesynthetic methods given above include 4-(2 furyl) 2 phenylthiazol 5ylacetic acid, 2 (4'-bromophenyl) 4 phenylthiazol 5 ylacetic acid, 2 (4'fluorophenyl) 4 phenylthiazol-S-ylacetic acid, 2 (4 nitrophenyl) 4phenylthiazol-S-ylacetic acid, a-(2,4-diphenylthiazol 5 yl)propionicacid ethyl ester, ,8-[2-(4-chlorophenyl) 4 phenylthiazol 5- yl]propionicacid ethyl ester, a-(2,4 diphenylthiazol-S- ly)propionic acid methylester, ,8-[2-(4'-chlorophenyl)- 4 phenylthiazol 5 yl]propionic acidmethyl ester, 2- (4' aminophenyl) 4 phenylthiazol 5 ylacetic acid,2-(4-isobutylphenyl)-4-phenylthiazol 5 ylacetic acid and2-(4-propoxyphenyl) 4 phenylthiazol-S-ylacetic acid.

What is claimed is:

1. A 2,4-diarylthiazole-5-polycarbon carboxylic acid compound having thestructural formula:

wherein R and R are each radicals of the group consisting of thienyl,furyl, naphthyl, phenyl, and phenyl bearing from one to two substituentsof the group consisting of (lower)alkyl, (lower)alkoxy, chloro, bromo,fluoro, di-(lower alkyl) amino, nitro, amino and trifluoromethyl, andwherein R is a radical from the group consisting of CH CO H, -CH CH COl-I, CHCH CO H, CH CO.NH -CH CO CH -CH C'O C H 2. A compound accordingto claim 1 which is 4(2'- thienyl) -2- (2-methylphenylthiazol-S-ylacetic acid.

3. A compound according to claim 1 which is 2-(4'- chlorophenyl)-4-(4methoxyphenyl)thiazol-5 ylacetic acid.

4. A compound according to claim 1 which is 2-(4'-chlorophenyl)-4-phenylthiazol-S-ylacetic acid.

5. A compound according to claim 1 which is 2-(4'-chlorophenyl)-4-(2'-thienyl)thiazol-S-ylacetic acid.

6. A compound according to claim 1 which is 2,4-di-(4'-methoxyphenyl)thiazol-S-ylacetic acid.

7. A compound according to claim 1 which is 4-(4'- methoxyphenyl)-2-(2'methylphenyl)thiazol S-ylacetic acid.

8. A compound according to claim 1 which is 2-(2-mcthylphenyl)-4-phenylthiazol 5-ylacetic acid.

9. A compound according to claim 1 which is 2-(3'-methylphenyl)-4-phenylthiazol-5-ylacetic acid.

10. A compound according to claim 1 which is 2-(4'-methoxyphenyl)-4-phenylthiazo1-5-ylacetic acid.

11. A compound according to claim 1 which is 2-(2-chlorophenyl)-4-phenylthiazol-5-ylacetic acid.

12. A compound according to claim 1 which is 2-(4'-methylphenyl)-4-phenylthiazol-S-ylacetic acid.

13. A compound according to claim 1 which is 2-(1'-naphthyl)-4-phenylthiazole-S-ylacetic acid.

14. A compound according to claim 1 which is 2-(3'-trifluoromethylphenyl)-4-phenylthiazol-S-ylacetic acid.

15. A compound according to claim 1 which is 4(2'-thienyl)-2-(4-methoxyphenyl)-thiazol-5-ylacetic acid.

16. A compound according to claim 1 which is 2-(2'-naphthyl)-4-phenyithiazol-5-ylacetic acid.

17. A compound according to claim 1 which is 2-(4'-methoXyphenyl)-4-(2-naphthyl)-thiazol-5-ylacetic acid.

18. A compound according to claim 1 which is B-[2- (4'-chlorophenyl-4-phenylthiazol-5-yl] -propionic acid.

19. A compound according to claim 1 which is 4-(1'-naphthyl)-2-phenylthiazol-5-ylacetic acid.

20. A compound according to claim 1 which is 4-(2-naphthyl)-2-phenylthiazol-S-ylacetic acid.

21. A compound according to claim 1 which is 2,4-dip'henylthiazol-S-ylacetic acid ethyl ester.

22. A compound according to claim 1 which is 2-phenyl-4-(4'-methoxyphenyl)thiazol-S-ylacetic acid ethyl ester.

23. A compound according to claim 1 which is 2-phenyl-4-(4'-chlorophenyl)thiazol-S-ylacetic acid ethyl ester.

24. A compound according to claim 1 which is 2,4-diphenylthiazol-S-ylacetic acid.

25. A compound according to claim 1 which is 2-phenyl-4-(4'-methoxyphenyl)thiazol-S-ylacetic acid.

26. A compound according to claim 1 which is 2-phenyl-4-(4'-ch1orophenyl)thiazol-S-ylacetic acid.

27. A compound according to claim 1 which is a-(Z,4-diphenylthiazol-5-yl)propionic acid.

28. A compound according to claim 1 which is 2-phenyl-4-(2'-t-hienyl)thiazol-S-ylacetic acid.

29. A compound according to claim 1 which is 2-phenyl-4-(4'-methylp'henyl)thiazol-S-ylacetic acid.

30. A compound according to claim 1 which is 2-(4-methoxyphenyl)-4-phenylthiazol 5 ylacetic acid ethyl ester.

31. A compound according to claim 1 which is 5-[2-(4-methoxyp-henyl)-4-phenylthiazol-5-yl]propionic acid.

32. A compound according to claim 1 which is ;8[2-(2'-methylphenyl)-4-phenylthiazol-5-yl]propionic acid.

33. A compound according to claim 1 which is 2,4-diphenylthiazol-S-ylacetic acid methyl ester.

34. A compound according to claim 1 which is )3-(2,4-diphenylthiazol-5-yl)propionic caid.

35. A compound according to claim 1 Which'is 2,4-diphenylthiazol-S-ylacetamide.

36. A compound according to claim 1 which is 4-(4'- chlorophenyl)-2-phenylthiazol-5 -ylacetamide.

References Cited FOREIGN PATENTS 1,099,389 1/ 1968 Great Britain.

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner U.S.Cl. X.R.

